New Cimlanod Trial Provides Insights Into Mechanistic Effects of Vasodilators in Heart Failure

This article refers to ‘Impact of vasodilators on diuretic response in patients with congestive heart failure: A mechanistic trial of cimlanod (BMS-986231)’ by P. Pellicori et al., published in this issue on pages 142–151. Heart failure (HF) is a clinical syndrome with wide range of aetiologies and underlying pathophysiological processes, making it a challenging disease entity to manage effectively. One of the hallmark features in many patients with both acute and chronic HF is pulmonary and systemic congestion due to salt and water retention. There have been numerous clinical trials evaluating medical therapies for chronic HF that have shown significant improvements in outcomes and these have translated into the latest guidelines.1-3 These strategies have broadly targeted renin–angiotensin–aldosterone system, neurohormonal activation and energetic efficiency, yet none of these strategies target congestion directly. The HF guidelines recommend use of diuretics in the presence of congestion,1, 2 and indeed loop diuretics, cornerstone treatment for water and salt retention, are amongst the most commonly used HF therapies, generally outperforming guideline-directed medical therapies that have a survival advantage. While mortality benefit has not been demonstrated in clinical trials for diuretic use in chronic HF, failure to achieve effective diuresis is generally associated with worse prognosis in HF. Prompt relief of symptoms of congestion, complicating volume overload in the setting of acute decompensation, remains a critical cornerstone of clinical cardiac failure management.4 Despite the obvious need for effective therapies, there remains a paucity of data to inform approaches to decongestion in patients with fluid overload beyond the use of loop diuretic therapy. While the use of loop diuretic agents continues to form the basis of current management, further progress in this area remains of major interest. This observation is reflected in recent studies addressing the use of acetazolamide in this patient population,5 reflecting the need for improved approaches to diuretic therapy in acute decompensation. In this context, vasodilator therapies, that can reduce cardiac preload and afterload and thus improve congestion have always seemed like a logical choice to enhance and complement other medication classes, especially the diuretics. Current guidelines addressing the use of vasodilator therapy recommend their use in patients without systemic hypotension with a view to alleviating congestive symptoms.1, 2 Various vasodilators, including nitroglycerin, sodium nitroprusside, serelaxin and nesiritide, have been assessed in several trials over the last decade and have found their role in the clinical management of acutely decompensated HF as adjuncts to diuresis, yet there are limited data which support their use, specifically with regard to mortality and renal function,6, 7 and almost no data about the precise mechanisms of their actions in the setting of HF-associated congestion. Indeed, in the absence of hypertension, the four large trials of vasodilator therapy (ASCEND-HF8 [nesiritide], TRUE-AHF9 [ularitide], RELAX-AHF-210 [serelaxin] and GALACTIC11 [nitrates and hydralazine]) have demonstrated no additional clinically significant benefit compared with standard therapy with loop diuretics to reverse congestion. The trials failed to demonstrate benefit in either short-term, symptomatic endpoints or longer-term outcomes. This lack of benefit was attributed to potentiation of renal water and salt retention despite or as a consequence of vasodilatation. Given the imperative to achieve optimal, early diuresis, and noting the lack of evidence base to support the use of conventional vasodilator therapy, new vasodilatory compounds are being explored. More recently, cimlanod (BMS-986231), a novel nitroxyl donor and vasodilator, has been evaluated in the STAND-UP AHF12 and StandUP Imaging13 trials. The STAND-UP AHF trial12 demonstrated that cimlanod was well tolerated, provided expected vasodilatory and decongestive effects, but those benefits did not persist beyond 48-h duration of treatment, while the StandUP Imaging trial13 showed improvements in left ventricular end-systolic dimensions and stroke volume indices comparable to nitroglycerin, without additional inotropic or lusitropic effects, in a small cohort of chronic HF patients. The most recent cimlanod study published by Pellicori et al.14 in this issue of the Journal is timely, building upon the STAND-UP programme and offers both the mechanistic insights into the limitations of vasodilator therapy in acutely decompensated HF and an explanation of the potential lack of benefit noted in clinical trials as well as previous observations of deleterious effects on renal function.14 This elegant study evaluated the more mechanistic effects of cimlanod on both the arterial and venous vasculature, renal function, and diuresis.14 Patients with left ventricular systolic dysfunction (left ventricular ejection fraction <40%) were administered intravenous furosemide after an infusion of the study drug or placebo. As expected, cimlanod was associated with reductions in blood pressure and systemic vascular resistance. Cimlanod also produced favourable effects on left ventricular filling pressures, left ventricular systolic function and natriuretic peptide levels.14 Intuitively, these haemodynamic effects as well as reductions in preload and afterload, as achieved by cimlanod, would be of benefit to patients with acute HF. Intriguingly, however, measures of blood volume increased with lower levels of urine volume and sodium excretion noted, implying the use of cimlanod impacts renal function and reduces the effectiveness of loop diuretic therapy in this setting.14 Potential mechanisms for this observation include reductions in renal perfusion in the setting of arteriolar vasodilatation. Reduction in renal perfusion exacerbates salt and water retention in acutely decompensated HF due to impaired diuretic delivery, increased sodium retention and reduced sodium filtration.4 The concept of impaired renal perfusion complicating vasodilator therapy is further supported by an analysis of the use of nesiritide which demonstrated impaired renal function in patients with acutely decompensated HF.7 Thus, the results of the current study finally provide more conclusive explanation for the lack of lasting effects of vasodilator therapies in HF. Yet, the study by Pellicori et al.14 is not without caveats: one of the key ones to consider is in this study, vasodilator was administered after diuretics were withheld for 48 h and only after cimlanod infusion were the patients re-challenged with small dose of diuretics. It is possible that concomitant diuretic administration and/or higher dose of furosemide might have counteracted the effects of cimlanod on water and salt excretion. Additionally, these were stable patients from the community with chronic congestion, rather than acutely decompensated HF patients which may have somewhat different renal response to diuretics. Furthermore, the patients had relatively preserved right heart function as well as renal function, thus representing a less advanced heart failure phenotype. Nevertheless, the principle of vasodilator therapy reducing efficacy of diuretic treatment has important clinical implications for dosing of diuretic agents in patients with acute features of volume overload, particularly in the setting of ischaemia or hypertension, as well as on development of future interventions for acute HF. Achieving synergistic effects on reduction in blood pressure, cardiac filling pressures and diuresis may potentially necessitate higher diuretic dosing regimens, the use of additional diuretic agents, such as thiazides and acetazolamide, or consideration of more alternative approaches such as ultrafiltration.15 Future study addressing the role of higher doses of diuretic therapy with concomitant use of vasodilator therapy may further inform approaches to acutely decompensated HF. As demonstrated in this study by Pellicori et al.,14 it is feasible to determine the effects of systemic vasodilator therapies on diuresis more completely in context of a clinical trial. Given the burden of HF, future directions could address the differential effects of vasodilator therapy options on the efficacy of furosemide treatment. This in turn may better place the use of vasodilator therapies in acutely decompensated HF into context and offer insights into more appropriate diuretic dosing regimens. The data presented by Pellicori et al.14 in this issue of the Journal demonstrate the benefit of such mechanistic studies in determining the optimal strategy for decongestion in acute HF by exploring the complex interplay between established cornerstones of management and challenging the existing role of vasodilator therapy in treatment. This study further highlights the importance of focussing more on assessing effects on salt and water balance, and potential interactions with diuretics in future studies of HF interventions, especially in the setting of decompensated/congestive HF. Aaron L. Sverdlov is supported by the National Heart Foundation of Australia Future Leader Fellowship (Award ID 106025). Doan T. M. Ngo is supported by the National Heart Foundation of Australia Future Leader Fellowship (Award ID 104814). Conflict of interest: none declared.